RNA exosome component EXOSC10 variants identified in a patient with premature ovarian insufficiency

Abstract Premature ovarian insufficiency (POI) impacts ~1–3.7% of women under the age of 40 globally and is characterised by an absence or complete loss of ovarian function. POI is clinically heterogenous in nature and researchers have identified 100 causative genes harbouring variants responsible for POI thus far. Genes identified to date include those associated with cell differentiation/development, mitochondrial maintenance, hormone receptors, transcription/translation factors, DNA repair/replication, and metabolic processes. Genes encoding cell components that facilitate these processes should therefore also be considered in POI gene candidature. The RNA exosome is a critical component in RNA processing, degradation, and biogenesis in eukaryotic cells. Catalytic activity of the RNA exosome is supplied by two subunits, DIS3 and EXOSC10. Dysregulation of RNA exosome function results in conditions known as exosomopathies that have a broad spectrum of phenotypic severity. RNA transcript regulation is essential in transcriptionally inactive maturing mammalian oocytes with its disruption negatively impacting meiosis and fertilization. Notably, oocyte depletion of Exosc10 significantly impacts the fertility of female mice. Herein we identified, via whole exome sequencing, the first instance of a human POI patient with an EXOSC10 homozygous missense variant. Using Drosophila melanogaster we modelled the impact of knockdown of the EXOSC10 ortholog, Rrp6, on both somatic and germline ovarian cells. We observed that Rrp6 is required in ovarian development in Drosophila. Due to the conserved role of EXOSC10 in fertility maintenance across species we contend that variants in EXOSC10 identified in POI patients may be causative.